The present invention relates to a process for preparing a compound which is useful as a starting material for the manufacture of an excellent antifungal agent whereby it is useful in the field of pharmaceutical industry.
In the International Laid-Open Gazette WO 96/11210, there is a disclosure on a method wherein 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione which is a starting material for the synthesis of antifungal agents of lipopeptide type is made to react with hydroxylamine hydrochloride to give methyl 4-[5-(4-pentyloxyphenyl)-isoxazol-3-yl]benzoate which is an aimed compound.
In the method mentioned in the above international patent application, 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione which is a starting material is made to react with hydroxylamine hydrochloride whereupon the aimed methyl 4-[5-(4-pentyloxyphenyl)-isoxazol-3-yl]benzoate is prepared. However, besides the aimed compound, its isomers are contaminated therein and, since separation of the aimed compound from the isomers is difficult, the yield of the aimed methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate is not fully satisfactory.
In view of the above, the present inventors have carried out an intensive investigation and, as a result, they have found a manufacturing method in which isomers of methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate are not produced whereby the above-mentioned problem in the conventional method has been solved. They have found a method for the manufacture of the related compounds as well.
The manufacturing method according to the present invention may be shown by the following reaction formulae. 
[Wherein
R1 is carboxy or protected carboxy;
R2 is lower alkoxy or higher alkoxy;
A1 is divalent aromatic ring, divalent heterocyclic group or divalent cyclo(lower)alkane; and
A2 is divalent aromatic ring, divalent heterocyclic group or divalent cyclo(lower)alkane.]
[Wherein
R1 is carboxy or protected carboxy;
R2 is lower alkoxy or higher alkoxy;
A1 is divalent aromatic ring, divalent heterocyclic group or divalent cyclo (lower) alkane; and
A2 is divalent aromatic ring, divalent heterocyclic group or divalent cyclo (lower) alkane.]
The characteristic feature of this manufacturing method is to carry out the reaction through the compound (II) or a salt from the starting compound (III) or a salt, and the said compound (II) or a salt is novel.
An preferable salt of the compounds (I), (II) and (III) is a conventional nontoxic mono- or di-salt, and its examples are metal salt such as alkaline metal salt (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.); ammonium salt; salt with an organic base (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.); addition salt with an organic acid (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); addition salt with an inorganic acid (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.); salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.); etc.
Suitable examples and explanations for various definitions included within the scope of the present invention mentioned in this specification both hereinabove and hereinafter will be mentioned in detail as follows.
Unless otherwise provided, xe2x80x9clowerxe2x80x9d is used to intend a group having 1 to 6 carbon atom(s).
Unless otherwise provided, xe2x80x9chigherxe2x80x9d is used to intend a group having 7 to 20 carbon atoms.
Suitable xe2x80x9clower alkoxyxe2x80x9d may include straight or branched chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, and the like. More preferably, it is (C3-C5) alkoxy and, most preferably, it is pentyloxy.
Suitable xe2x80x9chigher alkoxyxe2x80x9d may include straight or branched chain such as heptyloxy, octyloxy, 5-dimethyloctyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, eicosyloxy, and the like.
Suitable xe2x80x9cdivalent aromatic ringxe2x80x9d may include divalent group derived from benzene which may have lower alkyl (e.g., benzene, toluene, mesitylene, etc.), naphthalene, anthracene, etc., and more preferably, it is phenylene.
Suitable xe2x80x9cdivalent heterocyclic groupxe2x80x9d may include divalent group which is derived from:
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrroline, imidazole, pyrazole, pyridine, dihydropyridine, pyrimidine, pirazine, pyridazine, triazole (e.g., 4H-1,2,4-triazole, 1H-1,2,3-triazole, 2H-1,2,3-triazole, etc.), tetrazole (e.g., 1H-tetrazole, 2H-tetrazole, etc.), etc.;
saturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidine, piperidine, piperazine, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indole, isoindole, indolizine, benzoimidazole, quinoline, dihydroquinoline, isoquinoline, indazole, quinoxaline, dihydroquinoxaline, benzotriazole, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazole, isoxazole, oxadiazole (e.g., 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole, etc.), etc.;
saturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholine, sydnone, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazole, benzoxadiazole, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazole, isothiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, etc.), dihydrothiadiazole, etc.;
saturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidine, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thiophene, dihydrothiophene, dihydrodithiophene, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazole, benzothiadiazole, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing one oxygen atom, for example, furan, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing one oxygen atom and 1 or 2 sulfur atom(s), for example, dihydroxathiophene, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example, benzothiophene, benzodithiophene, etc.; and
unsaturated condensed heterocyclic group containing one oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiophene, etc.
Suitable xe2x80x9cdivalent cyclo(lower)alkanexe2x80x9d may include divalent group derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.
Suitable xe2x80x9cprotected carboxyxe2x80x9d may include a common one such as an esterified carboxy, and specific examples of the ester moiety in the said esterified carboxy are:
lower alkyl ester [e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.], suitably substituted lower alkyl ester, for example, lower alkanoyloxy lower alkyl ester [e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower alkanesulfonyl lower alkyl ester [e.g., 2-mesylethyl ester, etc.] or mono-(or di- or tri-)halo lower alkyl ester [e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.], etc.;
higher alkyl ester [e.g., heptyl ester, octyl ester, 3,5-dimethyloctylester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester, hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester, adamantyl ester, etc.];
lower alkenyl ester [e.g., C2-C6 alkenyl ester (e.g., vinyl ester, allyl ester, etc.)];
lower alkynyl ester [e.g., C2-C6 alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.)];
aryl lower alkyl ester which may have one or more suitable substituent(s) [e.g., phenyl lower alkyl ester which may have 1 to 4 lower alkoxy, halogen, nitro, hydroxyl, lower alkyl, phenyl or halo lower alkyl (e.g., benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.), etc.];
aryl ester which may have one or more suitable substituent(s) [e.g., aryl ester which may have 1 to 4 lower alkyl or halogen (e.g., phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.), etc.];
cycloalkyloxycarbonyloxy lower alkyl ester which may have lower alkyl [e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or 2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or 2-)[cycloheptyloxycarbonyloxy]ethyl ester, etc.]; and (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) lower alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or 2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-proyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.], etc.
and, among them, preferred ones are lower alkyl ester, lower alkanoyloxy lower alkyl ester, aryl lower alkyl ester which may have one or more suitable substituent(s), cycloalkyloxycarbonyloxy lower alkyl ester which may have lower alkyl, higher alkyl ester and (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)lower alkyl ester; more preferred one is lower alkyl ester; and most preferred one is methyl ester.
A preferred embodiment of the present invention is a manufacturing method in which the starting compound (III) is wherein
R1 is lower alkoxycarbonyl,
R2 is lower alkoxy,
A1 is divalent aromatic ring and
A2 is divalent aromatic ring,
and most preferred embodiment thereof is that
where
R1 is methoxycarbonyl,
R2 is pentyloxy,
A1 is phenylene and
A2 is phenylene.
Manufacturing method in accordance with the present invention will now be illustrated in detail as follows.
Step 1:
A compound (II) or a salt thereof can be manufactured by the reaction of a compound (III) or a salt thereof with an acid ammonium salt such as ammonium acetate, ammonium carbonate or ammonium formate.
This reaction is usually carried out in a solvent which does not affect the reaction such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), benzene, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, 1,2-dimethoxyethane, dioxane, ethyl acetate, diethyl ether or a mixture thereof.
Although there is no particular limitation for the reaction temperature, the reaction is usually carried out at room temperature or with warming or heating. The temperature is preferably 60 to 120xc2x0 C. or, more preferably, 90 to 100xc2x0 C.
Step 2:
A compound (I) or a salt thereof can be manufactured by the reaction of a compound (II) or a salt thereof with hydroxylamine or a salt thereof.
This reaction is usually carried out in a solvent which does not affect the reaction such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), benzene, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, methylene dichloride, chloroform, 1,2-dimethoxyethane, dioxane, ethyl acetate, diethyl ether or a mixture thereof.
Although there is no particular limitation for the reaction temperature, the reaction is usually carried out at room temperature or with warming or heating. The temperature is preferably 50 to 100xc2x0 C. or, more preferably, 55 to 60xc2x0 C.
The compounds (I) and (II) obtained according to the manufacturing method of the present invention can be separated and purified by common means such as disintegration, recrystallization, column chromatography or re-precipitation.
The compounds (I) and (II) obtained according to the manufacturing method of the present invention may contain one or more stereoisomer(s) such as geometrical isomer and optical isomers due to asymmetric carbon and double bond, and a method for the manufacture of such an isomer and a mixture thereof is also within a scope of the present invention.
In the known manufacturing method (WO 96/11210), an isomer of the aimed methyl 4-[5-(4-pentyloxyphenyl)-isoxazol-3-yl]benzoate was produced as a by-product, and separation of the aimed compound from this isomer was difficult.
No isomer for the aimed compound is produced from the compound (II) which is prepared according to the manufacturing method of the present invention and, therefore, purification of the aimed compound is easy, and the aimed compound having a high purity can be obtained in a high yield whereby the present invention is useful as a manufacturing method in an industrial scale.
Incidentally, the starting compound (III) can be easily manufactured from a less expensive compound and, accordingly, the present invention is advantageous in terms of cost as well.